Acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV), a retrovirus of the lentivirus family that was not discovered until the early 1980's. Knowing no boundaries, the virus has spread around the world to infect millions (Barre-Sinoussi et al., 1983; Gallo et al., 1984). HIV relentlessly destroys the immune system, the body's defense to invading pathogens. Those infected with HIV are susceptible to opportunistic infectious and neoplastic complications as a result of the inevitable manifestation of AIDS, thus succumbing to illness and death. The cost of the disease is incomprehensible; economic damages alone are staggering, but those for emotional and societal are beyond comprehension. The virus infects more victims every year, with little respite in sight, especially in undeveloped nations.
The virus not only weakens the barrier to opportunistic pathogen invasion, but also contributes to neoplastic complications. Through the suppression of the immune system, HIV facilitates the formation of several cancers, such as Kaposi's sarcoma (KS), non-Hodgkin's lymphomas (NHL) and cervical cancer (Prevention, 1992). HIV is thought to affect other cancers, such as Hodgkin's lymphomas, leiomyosarcoma, liver cancer, lung cancer, anal cancer, testicular cancer, oropharyngeal cancer, mieloma, and non-melanoma skin cancer (Beral and Newton, 1998).
When HIV infects a cell, it uses its reverse transcriptase (RT) to transcribe its RNA to DNA; the DNA then integrates into the host genome. This “proviral DNA” usurps cellular resources to cause the cell to produce additional HIV virions, which are then released from the cell. The HIV genome contains three major genes: env, gag, and pol. These genes encode the basic components of HIV. Env encodes the envelope precursor protein, gp160, that is protealyzed to 120 kd, producing the outer envelope glycoprotein gp120. Gp120 is responsible for tropism to CD4+ receptors; and transmembrane glycoprotein gp41, which catalyzes fusion of HIV to the membranes of the cell being infected. Gag encodes the matrix protein p17, the core capsid protein p24, and the nucleocapsid protein p7. Pol encodes various enzymes, including the reverse transcriptase p66, integrase p32, and protease p11.
Because RT is a necessary component of HIV proliferation, it has become a primary target for therapeutic attack. Several RT inhibitors are currently in use in the US (See Tables 1 and 3). Based on their mechanisms of action, RT inhibitors are divided into two groups: (1) non-nucleoside and (2) nucleoside analog inhibitors. The non-nucleoside inhibitors have diverse chemical structures, but all bind a hydrophobic pocket in RT that is adjacent to the polymerase active site. This binding is thought to reduce the enzymatic activity of RT through direct steric perturbations, inhibiting DNA replication. Because of the rapid appearance of drug resistance, non-nucleoside inhibitors are seldom used clinically (Wei et al., 1995).
Nucleoside analog inhibitors are pro-drugs and must be converted into the active form, the 5′-triphosphate, by cellular enzymes to be effective. Nucleoside analog inhibitors lack the 3′-hydroxyl groups required for DNA chain extension during reverse transcription. Incorporation of these molecules into the growing polynucleotide by RT causes premature chain termination, thereby inhibiting DNA replication.
In addition to the RT inhibitors, molecules that target the HIV protease (Table 2) substantially reduce the death rate (Palella et al., 1998). If either protease inhibitors or RT inhibitors are administered alone, HIV quickly mutates, becoming resistant to the drugs and compromising treatment. Combination therapy circumvents this problem by simultaneously administering multiple drugs. Such drug “cocktails” usually contain three inhibitors: one directed against protease and two against RTs. In some patients, this combinatorial weapon reduces the amount of virus in the body to an undetectable level; but this result is hardly universal. The battle against AIDS continues to rage and claim casualties.
Current battle plans to fight HIV infection have significant drawbacks. First, combination therapy is expensive, and the number of inhibitors, especially those of RTs, is limited. Second, drug administration is a life-long requirement: HIV levels increase upon arresting therapy. Third, a patient must obey a strict schedule of administration. If the strict schedule is not adhered to, viral strains simultaneously resistant to multiple drugs arise, again compromising therapy. Finally, economic considerations preclude treatment of those people without sufficient resources, especially in developing countries, where the largest population of HIV infected patients live.
TABLE 1Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIS)DrugAdult dosingSide effects1NotesRetrovir ® (AZT),300 mg × 2/dayNausea; stomach discomfort; headache; insomnia;by GlaxoSmithKlinemuscle wasting; anemia; neutropenia(Research TrianglePark, NC)Epivir ® (3TC), by300 mg × 1/day orNauseaAlso used to treatGlaxoSmithKline150 mg × 2/daypatients infected with theHepatitis B Virus (HBV),but at a different dose. Ifdually infected, the HIVdosage is used.Combivir ®300 mg AZT + 150 mgNausea; loss of appetite; headache; fatigue; stomach(AZT + 3TC), by3TC × 2/daydiscomfort; muscle wasting anemia; neutropeniaGlaxoSmithKlineTrizivir ®300 mg AZT + 150 mgSimilar side effects to Retrovir (AZT), Epivir (3TC),Subject must weigh(AZT + 3TC +3TC + 300 mgand Ziagen (abacavir).greater than 90 poundsabacavir), byabacavir × 2/day(40 kg).GlaxoSmithKlineZiagen ®300 mg × 2/dayNausea; vomiting; diarrhea; loss of appetite; insomniaTake with or without(abacavir), bySerious allergic reactions in about 3-5% of patients.food.GlaxoSmithKlineVidex ® (ddI):200 mg × 2/day orPeripheral neuropathy; nausea; diarrhea; vomiting;Twice-daily dosing isbuffered versions,400 mg × 1/dayheadache; rash; pancreatitis.more effective. Possibleby Bristol-Myersincreased side effects ifSquibb (New York,taken with tenofovirNY)(Viread).Videx ® EC (ddI):400 mg × 1/day; ifNumbness, tingling, or pain in the hands or feetdelayed-releasesubject weighs less than(peripheral neuropathy, seen in 15% of patients);capsules, by Bristol-133 lbs. (60 kg), thennausea; diarrhea; vomiting; headache; rash; pancreatitis.Myers Squibb250 mg × 1/dayPossible increased side effects if taken with tenofovir(Viread).Zerit ® (d4T), by40 mg every 12 hoursPeripheral neuropathy; nausea; diarrhea; vomiting;Cannot be taken withBristol-Myersheadache; rash; pancreatitis; lactic acidosis.Retrovir (AZT) orSquibbCombivir (AZT + 3TC).Hivid ® (ddC), by0.75 mg every 8 hoursPeripheral neuropathy, nausea; mouth ulcers.Hoffmann-La Roche(Nutley, NJ)Viread ™ (tenofovir300 mg × 1/dayNausea, vomiting, diarrhea, and flatulence.If taken with ddI (VidexDF), by Gileador Videx EC), it canSciences (Fosterincrease ddI levels in theCity, CA)blood by as much as60%, causing increasedddI side effects.1Long-term side effects of NRTIs. NRTIs have been associated with damage to the mitochondria. This damage may cause low red and white blood cell counts, muscle pain and wasting (particularly in the arms and legs), fatigue, peripheral neuropathy, and more rarely, serious liver (lactic acidosis) or pancreas problems.*“x n” where n is an number, refers to administering the indicated dose n times a day.
TABLE 2Protease inhibitorsDrugAdult dosingSide effects2NotesFortovase ®1600 mg × 2/day, orNausea; diarrhea; stomach discomfort; insomnia;Should be administered within(saquinavir soft gel1200 mg × 3/dayheadache; increased liver enzyme levelsone hour after subject hascapsules), byingested a meal containing atHoffmann-La Rocheleast 28 g fat.Norvir ® (ritonavir),600 mg × 2/dayNausea; vomiting; diarrhea; loss of appetite; stomachHigh fat foods reduce sideby Abbottdiscomfort; oral tingling and numbness; increased livereffects. Used at lower doses toLaboratories (Abbottenzyme levelsenhance other proteasePark, IL)inhibitors.Crixivan ®800 mg every 8 hoursKidney stones (seen in 6-8% of patients); nausea;Subject needs to take(indinavir), by Merckvomiting; diarrhea; stomach discomfort; headache;precautions against kidney& Co.insomnia; rash; back painstones, such as drinking atleast 48 ounces water daily.Viracept ®750 mg × 3/day, orDiarrhea; nausea; stomach discomfort; gas; rash;Food encourages absorption.(nelfinavir), by1250 mg × 2/ dayincreased liver enzyme levelsAgouronPharmaceuticals (SanDiego, CA)Agenerase ®1200 mg × 2/dayRash; diarrhea; nausea; vomiting; oral tingling andHigh-fat meals should be(amprenavir), bynumbnessavoided.GlaxoSmithKlineKaletra ® (lopinavir +1000 mg lopinavir/100 mgDiarrhea; nausea; feeling week/tired; headache;If combining with Sustiva ®ritonavir), by Abbottritonavir × 2/daypancreatitis(efavirenz), dose should beLaboratoriesincreased to 4 capsules,twice a day.2Long-term side effects of protease inhibitors. Use of protease inhibitors may be associated with changes in blood sugar levels (and rarely, development of diabetes), elevations in blood fat levels, and lipodystrophy. There have been reports of uncontrolled bleeding in hemophiliacs.
TABLE 3Non-nucleoside reverse transcriptase inhibitors (NNRTIs)DrugAdult dosingSide effectsNotesViramune ®200 mg x 2/dayRash; stomach upset;(nevirapine), byheadaches; increased liverRoxane Laboratoriesenzyme levels(Columbus, OH)More rarely: hepatitisRescriptor ®400 mg × 3/dayRash; headache; fatigue;(delavirdine), bystomach upset; elevated liverAgouronenzymesPharmaceuticalsSustiva ® (efavirenz),600 mg × 1/dayRash; drowsiness; insomnia;Administration should be taken at bedtime toby Bristol-Myersconfusion; inability tominimize dizziness, drowsiness and impairedSquibbconcentrate; dizziness; vividconcentration.dreams; nausea; stomachdiscomfort; fever; insomnia;elevated liver enzymes.